The University of Michigan proposes to establish a multidisciplinary program project in gene therapy for cancer. This program is based upon the existing strengths in molecular biology and cancer immunotherapy present at this institution. Recently, it has been found that the immunogenicity of tumors can be altered by genetic modification such that the innate host immune response can be up-regulated against native or parental tumor antigens. Drawing from these observations, we propose to examine the immunobiology of the response to gene modified tumors in experimental models and in clinical therapy studies. This program is organized into three interactive projects, a research core and an administrative core. Project 1 entitled, "Immune response to genetically modified tumors", will be directed by Suyu Shu, Ph.D. This project will examine the T cell immune response to tumors with diverse immunogenicities by the transduction of allogeneic MHC or cytokine genes. In particular, the antitumor reactivity of T cells isolated from hosts bearing genetically modified tumors will be evaluated in adoptive immunotherapy studies. Project 2 entitled. "Clinical therapy utilizing immune T cells induced by gene-modified human cancers" will be led by Alfred Chang, M.D. This will involve a clinical trial of adoptive immunotherapy of cancer with anti-CD3/IL-2 activated lymph node cells after in vivo priming with tumors transfected with allogeneic class I MHC or TNF alpha genes. The immune reactivity of the adoptively transferred cells will be examined with respect to antitumor efficacy, antigen specificity and in vivo homing. Project 3 entitled, :Immunotherapy by in vivo gene transfer into tumors" will be directed by Gary Nabel, M.D., Ph.D. This project is focused on a novel approach of direct gene transfer in vivo by the intratumoral inoculation of liposome/DNA complexes. In particular, the immune response induced by established tumors modified by the in vivo transfer of a gene encoding an allogeneic class I MHC glycoprotein will be examined both experimentally and clinically. Methods to enhance the host antitumor response elicited by this innovative approach will be explored. The research core is entitled, "Liposome/DNA Research Core" and will be directed by Leaf Huang, Ph.D., University of Pittsburgh. This core will serve a research and service function. Its research unction will be to optimize gene transfer utilizing liposomes as vehicles and to examine target specific transfection with specific monoclonal antibodies. The service function will be to provide cationic liposome reagents necessary for the investigations in the projects. The research aims of these projects and core are highly integrated with the ultimate goal to develop innovative cancer treatment approaches. A major strength of this program is the ability to rapidly translate experimental observations into clinical studies. These investigators already have clinical studies of adoptive immunotherapy and gene therapy underway.